Chronic rejection of vascularized allografts is a poorly understood process which prevents organ transplantation from being more than a relatively short-term treatment for a lifetime disease. This Program Project represents an integrated approach to studying the immunological and pathophysiological mechanisms which eventually lead to graft deterioration and failure over time. The research proposal consists of three projects which address different but interrelated aspects of chronic transplant injury. Project 1 will use a well established rat model of chronic renal allograft rejection to investigate the central role of the macrophage and fibrosis inducing macrophage derived products in this type of protracted allograft injury. It will address how both antigen dependent and antigen independent mechanisms are involved synergistically in the initiation and maintenance of chronic graft injury, and what role specific cytokines play at early and late periods post-transplant. The relevance of the animal studies to human renal allograft injury will be evaluated in recipients at "high risk" for chronic rejection. Project 2 focuses on two recently defined aspects of T cell alloimmunity which have only recently been defined, the indirect pathway of allorecognition and T cell co-stimulation. Peptides derived from immunogenic domains of major histocompatibility complex molecules are selectively recognized via the indirect pathway and will be used as probes to define the role of this mode of antigen recognition in chronic rejection. The importance of T cell co-stimulation through CD28-B7 interaction will be studied by using selective inhibitors of this pathway. Project 3 will use transgenic mice with regulatable NFkB expression as donors of cardiac allografts in order to determine whether the upregulation or downregulation of gene expression in donor endothelium can modulate the chronic process and as recipients to allow analysis of the contribution of host cells to vascular injury; NFkB is an early gene which in turn induces the expression of many of the effector cytokines to be investigated. The Immunopathology Core will provide an expert resource for the three projects. Consistent interpretation of tissue immunopathology will facilitate the integration of conclusions derived from each of the individual projects. The Administrative Core will coordinate both the scientific efforts and budget management of the three research teams.